Interferon-gamma inducing factor (IGIF) is an approximately 18-kDa polypeptide that stimulates T-cell production of interferon-gamma (IFN-.gamma.). IGIF is produced by activated Kupffer cells and macrophages in vivo and is exported out of such cells upon endotoxin stimulation. Thus, a compound that decreases IGIF production would be useful as an inhibitor of such T-cell stimulation which in turn would reduce the levels of IFN-.gamma. production by those cells.
IFN-.gamma. is a cytokine with immunomodulatory effects on a variety of immune cells. In particular, IFN-.gamma. is involved in macrophage activation and Th1 cell selection (F. Belardelli, APMIS, 103, p. 161 (1995)). IFN-.gamma. exerts its effects in part by modulating the expression of genes through the STAT and IRF pathways (C. Schindler and J. E. Darnell, Ann. Rev. Biochem., 64, p. 621 (1995); T. Taniguchi, J. Cancer Res. Clin. Oncol., 121, p. 516 (1995)).
Mice lacking IFN-.gamma. or its receptor have multiple defects in immune cell function and are resistant to endotoxic shock (S. Huang et al., Science, 259, p. 1742 (1993); D. Dalton et al., Science, 259, p. 1739 (1993); B. D. Car et al., J. Exp. Md., 179, p. 1437 (1994)). Along with IL-12, IGIF appears to be a potent inducer of IFN-.gamma. production by T cells (H. Okamura et al., Infection and Immunity, 63, p. 3966 (1995); H. Okamura et al., Nature, 378, p. 88 (1995); S. Ushio et al., J. Immunol., 156, p. 4274 (1996)).
IFN-.gamma. has been shown to contribute to the pathology associated with a variety of inflammatory, infectious and autoimmune disorders and diseases. Thus, compounds capable of decreasing IFN-.gamma. production would be useful to ameliorate the effects of IFN-.gamma. related pathologies.
The biological regulation of IGIF and thus IFN-.gamma. has not been elucidated. It is known that IGIF is synthesized as a precursor protein, called "pro-IGIF". It has been unclear, however, how pro-IGIF is cleaved and whether its processing has biological importance.
Accordingly, compositions and methods capable of regulating the conversion of pro-IGIF to IGIF would be useful for decreasing IGIF and IFN-.gamma. production in vivo, and thus for ameliorating the detrimental effects of these proteins which contribute to human disorders and diseases.
Another cytokine, IL-1.beta., is produced as an inactive precursor (pre-IL-1.beta.) which is proteolytically cleaved into an active, mature form (IL-1.beta.) by a cysteine protease called interleukin-1.beta. converting enzyme (ICE). ICE is a member of a larger family of cysteine proteases, called the ICE/CED-3 family, which share common structural and functional features. See, e.g., P. A. Henkarp, Immunity, 4, p. 195 (1996); D. W. Nicholson, Nature Biotechnology, 14, p. 297 (1996).
However, ICE and other members of the ICE/CED-3 family have not previously been linked to the conversion of pro-IGIF to IGIF or to IFN-.gamma. production in vivo.